In this proposal, I aim to study the mechanism HIV-1 uses to escape from a new class of inhibitors of its replication. These compounds, termed CCR5 inhibitors, bind to the host cellular protein CCR5, which is a coreceptor for HIV-1 entry into target cells. AIDS is now a global pandemic. Viruses resistant to the current classes of anti-retroviral drugs are now becoming commonplace in areas where these drugs have been used extensively. Thus, it is important to study a new class of HIV-1 inhibitors that will hopefully be used to supplement existing therapies. We need to understand how HIV-1 can evade CCR5 inhibitors. This project will be carried out by characterizing the mechanism of escape of a previously described virus that was forced :o become resistant to a CCR5 inhibitor. The main tool used will be a panel of site-directed mutants of CCR5. They will be used to study how they interact with soluble envelope glycoproteins from the parental and resistant viruses; their ability to mediate infection by HIV-1; and their ability to bind to anti-CCR5 monoclonal antibodies. In all of these assays, I will use parental and inhibitor-resistant viruses, in the presence or absence of inhibitors.